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J. Biol. Chem., Vol. 283, Issue 18, 12538-12545, May 2, 2008

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Mouse EP3 , β, and Receptor Variants Reduce Tumor Cell Proliferation and Tumorigenesis in Vivo^*

Ines M. Macias-Perez, Roy Zent^¶||, Monica Carmosino, Matthew D. Breyer, Richard M. Breyer, and Ambra Pozzi^||1

From the Departments of Medicine (Division of Nephrology), Cancer Biology, and ^¶Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232 and the ^||Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee 37232

Prostaglandin E₂, which exerts its functions by binding to four G protein-coupled receptors (EP1-4), is implicated in tumorigenesis. Among the four E-prostanoid (EP) receptors, EP3 is unique in that it exists as alternatively spliced variants, characterized by differences in the cytoplasmic C-terminal tail. Although three EP3 variants, , β, and , have been described in mice, their functional significance in regulating tumorigenesis is unknown. In this study we provide evidence that expressing murine EP3 , β, and receptor variants in tumor cells reduces to the same degree their tumorigenic potential in vivo. In addition, activation of each of the three mEP3 variants induces enhanced cell-cell contact and reduces cell proliferation in vitro in a Rho-dependent manner. Finally, we demonstrate that EP3-mediated RhoA activation requires the engagement of the heterotrimeric G protein G₁₂. Thus, our study provides strong evidence that selective activation of each of the three variants of the EP3 receptor suppresses tumor cell function by activating a G₁₂-RhoA pathway.

Received for publication, January 4, 2008 , and in revised form, January 23, 2008.

^* This work was supported by National Institutes of Health Grants RO1-CA94849 (to A. P.), RO1-DK074359 (to A. P.), and RO1-DK69921 (to R. Z.), by a merit award from the Department of Veterans Affairs (to R. Z.), by National Institutes of Health Grant DK37097 (to R. M. B. and M. D. B.), and by funding from Philip Morris USA Inc. (to A. P. and R. M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine, Division of Nephrology, Medical Center North, B3109, Vanderbilt University, Nashville, TN 37232. Tel.: 615-322-4637; Fax: 615-322-4690; E-mail: ambra.pozzi{at}vanderbilt.edu.

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